Insulin resistance in obesity and aging is an expression of a common form of non-insulin dependent diabetes mellitus. We have been studying the regulation of insulin receptor phosphorylation in an in vitro system in an attempt to understand how this regulation can be manipulated in vivo as an approach to the treatment for elderly diabetics. We have demonstrated rapid phosphorylation and dephosphorylation of the insulin receptor in solubilized membranes. Dephosphorylation of the insulin receptor by membrane-bound protein tyrosine phosphatases was specifically and substantially reduced by the presence of several new inhibitory peptides. The same peptides were ineffective in preventing a range of other (non-specific broad spectrum) phosphatases from dephosphorylating insulin receptors. The high specificity of action of several of these peptides was shown; they were effective with insulin receptor but not with the closely related EGF receptor. With intact cells, results were consistent with observations made with the permeabilized cell system.